SUMMARY The overarching goal of this project is to deepen our understanding of the aging brain in a well characterized community-based longitudinal prospective cohort study. The Adult Changes of Thought (ACT) study enrolled a cohort of 2,581 Group Health participants in 1994-1996, an expansion cohort of 811 in 2000-2002, and in 2005 began continuous enrollment to keep 2,000 people alive and at risk for dementia outcomes; total enrollment to date is more than 5,700. Extensive and unmatched clinical and research study data are available for study participants. Autopsy consent is sought; 850 autopsies have been completed to date, and more than a third of active participants have signed autopsy consents. Investigators propose three aims. Aim 1 addresses MULTIMORBIDITY: the single and joint effects of blood pressure, glucose, and cholesterol, and their treatments, on the aging brain. Outcomes include time to dementia and Alzheimer?s disease, cognitive functioning, standard neuropathological indices, and newly developed quantitative measures of regional A?, tau, and synaptophysin. This aim leverages important methodological innovations, including hierarchical Bayesian modeling of exposure trajectories to incorporate sporadically collected clinical data, modern psychometric approaches to cognitive data, use of marginal structural models to account for selection bias for autopsy studies, new criteria for neuropathological assessment of AD, and the newly developed quantitative measures of neuropathology. Aim 2 addresses RESILIENCE: why some people do well despite factors associated with doing poorly. Aim 2a addresses the role of physical activity on trajectories of cognition and physical performance, using accelerometers to address the amount and type of activity associated with protection. Aim 2b addresses factors associated with living to age 85 while preserving cognition and mobility, specifically focusing on physical activity and on medical comorbidity. Aim 2c addresses factors associated with avoiding dementia despite accumulation of neuropathology. In particular, Aim 2c will focus on synaptic contents, applying flow cytometry of a synaptosome preparation. Aim 3 addresses a LIVING LABORATORY: continuing to serve as a resource to researchers around the world.